How should potassium supplementation, Ativan (lorazepam), oxycodone, and cefadroxil be managed in a patient starting Paxlovid (nirmatrelvir/ritonavir)?

Management of Potassium Supplementation, Ativan, Oxycodone, and Cefadroxil with Paxlovid

Oxycodone must be temporarily discontinued or dose-reduced by at least 50-75% during the 5-day Paxlovid course due to ritonavir's potent CYP3A4 inhibition causing dangerous opioid accumulation and respiratory depression risk; Ativan (lorazepam) can be continued without dose adjustment as it undergoes glucuronidation rather than CYP3A metabolism; potassium supplementation and cefadroxil have no significant interactions and can be continued unchanged. 1, 2, 3

Oxycodone Management (High-Risk Interaction)

Ritonavir in Paxlovid is a potent CYP3A4 inhibitor that dramatically increases oxycodone plasma concentrations, creating serious risk of opioid toxicity including respiratory depression, excessive sedation, and potential fatality. 1, 2

Recommended approach:

• Discontinue oxycodone entirely during the 5-day Paxlovid course if clinically feasible 2, 4
• If pain control is essential, reduce oxycodone dose by 50-75% and monitor intensively for sedation, respiratory depression, and altered mental status 1, 4
• Consider switching to non-CYP3A metabolized alternatives (acetaminophen, NSAIDs if appropriate) during Paxlovid treatment 2
• Resume normal oxycodone dosing 2-3 days after completing Paxlovid to allow ritonavir washout 2

A case report documented acute encephalopathy in an elderly patient receiving Paxlovid with concurrent narcotics, demonstrating real-world toxicity from this interaction. 4

Ativan (Lorazepam) Management (Low-Risk)

Lorazepam is metabolized via glucuronidation (UGT enzymes), not CYP3A4, making it one of the safer benzodiazepines to continue with Paxlovid. 2, 3

Key considerations:

• No dose adjustment required for lorazepam during Paxlovid treatment 2, 3
• Lorazepam is preferred over CYP3A-metabolized benzodiazepines (alprazolam, midazolam, triazolam) which are contraindicated or require major dose reductions with ritonavir 2, 3
• Monitor for additive sedation, particularly in elderly patients or those on multiple CNS depressants 4

However, the case report of encephalopathy involved benzodiazepines combined with narcotics, emphasizing caution with polypharmacy even when individual interactions appear manageable. 4

Potassium Supplementation (No Interaction)

Potassium supplements have no pharmacokinetic interaction with Paxlovid as they are not metabolized by CYP enzymes or transported by P-glycoprotein. 2, 3

• Continue potassium supplementation at current dose without adjustment 3
• Standard monitoring of serum potassium levels as clinically indicated, unrelated to Paxlovid use 3

Cefadroxil (No Interaction)

Cefadroxil, a first-generation cephalosporin antibiotic, is renally eliminated without significant CYP3A4 metabolism and has no documented interaction with ritonavir. 3

• Continue cefadroxil at prescribed dose without modification 3
• No additional monitoring required beyond standard antibiotic therapy assessment 3

Critical Monitoring Parameters

For patients continuing any medications with Paxlovid, monitor for:

• Excessive sedation, confusion, or altered mental status (particularly with oxycodone if continued at reduced dose) 4
• Respiratory rate and oxygen saturation (if opioids continued) 2, 4
• Signs of opioid withdrawal (if oxycodone discontinued abruptly in opioid-dependent patients—consider very low bridging doses) 2

Common Pitfalls to Avoid

• Do not assume all benzodiazepines are safe like lorazepam—alprazolam and midazolam are contraindicated with Paxlovid 2, 3
• Do not continue full-dose oxycodone thinking a 5-day course is too short to matter—ritonavir's CYP3A4 inhibition is immediate and potent 1, 2
• Do not forget that ritonavir effects persist 2-3 days after the last Paxlovid dose due to its half-life, requiring continued caution during this washout period 2
• Elderly patients are at particularly high risk for drug interaction complications, as demonstrated in the encephalopathy case report 4